Technical Field
The present disclosure relates to compounds having a tyrosine-based structure with prenyl group substitution and bearing properties for abrogating TRAIL resistance. A method for producing the compounds, and a pharmaceutical composition comprising one or more of the compounds is presented.
Description of the Related Art
The “background” description provided herein is for the purpose of generally presenting the context of the disclosure. Work of the presently named inventors, to the extent it is described in this background section, as well as aspects of the description which may not otherwise qualify as prior art at the time of filing, are neither expressly or impliedly admitted as prior art against the present invention.
Cancers are genetic diseases that result from the deregulation of cell growth and cell death pathways due to genomic alterations. Apoptosis, the process of programmed cell death, is a genetically programmed biochemical process that removes unwanted cells and maintains tissue homeostasis. Tumor necrosis factor related apoptosis inducing ligand (TRAIL), a tumor necrosis factor (TNF) family member, activates apoptotic pathways selectively in cancer cells through binding on the death receptors, DR4 and DR5 [Pitti, R. M.; Marsters, S. A.; Ruppert, S.; Donahue, C. J.; Moore, A.; Ashkenazi, A. J. Biol. Chem. 1996, 271, 12687-12690.; and Wiley, S. R.; Schooley, K.; Smolak, P. J.; Din, W. S.; Huang, C-P.; Nicholl, J. K.; Sutherland, G. R.; Smith, T. D.; Rauch, C.; Smith, C. A.; Goodwin, R. G. Immunity 1995, 3, 673-682.; and Ashkenazi, A. Nat. Rev. Cancer 2002, 2, 420-430.; and Pan, G.; Ni, J.; Wei, Y. F.; Yu, G.; Gentz, R.; Dixit, V. M. Science 1997, 277, 815-818.; and Schneider, P.; Thome, M.; Burns, K.; Bodmer, J. L.; Hofmann, K.; Kataoka, T.; Holler, N.; Tschopp, J. Immunity 1997, 7, 831-836.; and Chaudhary, P. M.; Eby, M.; Jasmin, A.; Bookwalter, A.; Murray, J.; Hood, L. Immunity 1997, 7, 821-830.; and Wu, G. S.; Burns, T. F.; McDonald, E. R 3rd.; Jiang, W.; Meng, R.; Krantz, I. D.; Kao, G.; Gan, D. D.; Zhou, J. Y.; Muschel, R.; Hamilton, S. R.; Spinner, N. B.; Markowitz, S.; Wu, G.; el-Deiry, W. S. Nat. Genet. 1997, 17, 141-143. —each incorporated herein by reference in its entirety]. After initiation by the death receptor pathway, TRAIL-induced apoptosis results in activation of effector caspase-3, death-inducing signaling complex (DISC) formation and proteolytic activation of caspase-8 [Ashkenazi, A.; Dixit, V. M. Curr. Opin. Cell. Biol. 1999, 11, 255-260. —incorporated herein by reference in its entirety].
TRAIL has emerged as an attractive antineoplastic agent due to its remarkable ability to selectively kill tumoral cells while leaving normal cells unscathed [Ishibashi, M.; Ohtsuki, T. Med. Res. Rev. 2008, 28, 688-714. —incorporated herein by reference in its entirety]. Unlike the other members of the TNF superfamily, in vivo administration of TRAIL has been proven to be safe [Ahmed, F.; Toume, K.; Sadhu, S. K.; Ohtsuki, T.; Arai, M. A.; Ishibashi, M. Org. Biomol. Chem. 2010, 8, 3696-3703. —incorporated herein by reference in its entirety]. However, in the case of highly malignant tumors, a reasonable number of cancer cells have intrinsic or acquired resistance to TRAIL induced apoptosis [Zhang, L.; Fang, B. Cancer Gene Ther. 2005, 12, 228-237. —incorporated herein by reference in its entirety]. Therefore, the discovery of compounds that can abrogate TRAIL resistance has attracted a great deal of attention in anticancer drug discovery.
In a recent study, bioassay-guided fractionation of Streptomyces sp. IFM 10937, has led to the isolation of a new tyrosine derivative, compound 1 (FIG. 1) [Ahmed, F.; Ohtsuki, T.; Aida, W.; Ishibashi, M. J. Nat. Prod. 2008, 71, 1963-1966. —incorporated herein by reference in its entirety]. Compound 1 was evaluated for its activity in overcoming TRAIL resistance in AGS (human gastric adenocarcinoma) cells. Combined treatment of 75 or 150 μM of compound 1 and 100 ng/mL TRAIL with AGS cell lines reduced cell viability to 77±7% and 67±5% of control levels (p<0.01), respectively, which suggested a possible synergism between the two agents.
In view of the forgoing and ongoing efforts towards the total synthesis of bioactive natural products [Arafeh, K. M.; Ullah, N. Nat. Prod. Commun. 2009, 4, 925-926.; and Ullah, N.; Arafeh, K. M. Tetrahedron Lett. 2009, 50, 158-160.; and Ullah, N.; Haladu, S. A. Nat. Prod. Commun. 2010, 5, 1077-1080.; and Ullah, N.; Haladu, S. A.; Moosa, B. A. Tetrahedron Lett. 2011, 52, 212-214. —each incorporated herein by reference in its entirety] one object of the present disclosure is to provide a method for producing compounds of formula (I), such as compound 1 and compound 2, which bear TRAIL resistance abrogating properties via robust, reproducible and economical synthetic methods including rearrangement and olefin cross metathesis. A further aim of the present disclosure is pharmaceutical compositions comprising compounds of formula (I) such as compound 1 and compound 2.